title: Effects of dietary flavonoids on the transport of cimetidine via P-glycoprotein and cationic transporters in Caco-2 and LLC-PK1 cell models.
abstract: 1. The hypotheses tested were to study cimetidine as a substrate of P-glycoprotein (P-gp) and organic cation transport systems and the modulatory effects of eight flavonoid aglycones and glycosides on these transport systems using Caco-2 and LLC-PK1 cells. 2. Transport and uptake experiments of (20 microM) (3)H-cimetidine were performed with and without co-exposure to quercetin, quercetrin, rutin, naringenin, naringin, genistein, genistin, and xanthohumol. Co-treatment decreased basolateral to apical (B to A) permeability (P(app)) of cimetidine from 2.02 to 1.24 (quercetin), 1.06 (naringenin), 1.24 (genistein), and 0.96 (xanthohumol) x 10(-6) cm s(-1) in Caco-2 cells and from 10.76 to 1.65 (quercetin), 2.05 (naringenin), 2.88 (genistein), and 1.95 (xanthohumol) x 10(-6) cm s(-1) in LLC-PK1 cells. Genistin significantly reduced B to A P(app) of cimetidine to 1.24 x 10(-6) cm s(-1) in Caco-2 cells. Basolateral intracellular uptake rate of cimetidine was enhanced 145-295% when co-treated with flavonoids. Co-treatment with P-glycoprotein and organic cation transporter inhibitors, verapamil and phenoxybenzamine, resulted in reduced B to A permeability and slower basolateral intracellular uptake rate of cimetidine. Intracellular uptake rate of (14)C-tetraethylammonium (TEA) was reduced in the presence of quercetin, naringenin and genistein in LLC-PK1 cells. 3. In conclusion, quercetin, naringenin, genistein, and xanthohumol reduced P-gp-mediated transport and increased the basolateral uptake rate of cimetidine. Quercetin, naringenin, genistein, but not xanthohumol, reduced intracellular uptake rate of TEA in LLC-PK1 cells. These results suggest that flavonoids may have potential to alter the disposition profile of cimetidine and possibly other therapeutics that are mediated by P-gp and/or cation transport systems.
authors.affiliation: Drug Safety and Disposition, Eisai Research Institute, Andover, MA, USA.
authors.forename: J-S
authors.initials: JS
authors.lastname: Taur
authors.forename: R
authors.initials: R
authors.lastname: Rodriguez-Proteau
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D002927:Cimetidine / Q000378:metabolism*; D044950:Flavanones / Q000378:metabolism / Q000494:pharmacology; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D019833:Genistein / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D018374:LLC-PK1 Cells; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D011427:Propiophenones / Q000378:metabolism / Q000494:pharmacology; D011794:Quercetin / Q000378:metabolism / Q000494:pharmacology; D013552:Swine; D019789:Tetraethylammonium / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044950:Flavanones; D005419:Flavonoids; D027701:Organic Cation Transport Proteins; D011427:Propiophenones; D019789:Tetraethylammonium; D002927:Cimetidine; D011794:Quercetin; D019833:Genistein; C005273:naringenin; C104536:xanthohumol